Classical Hodgkin lymphoma

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81 regimens on this page
128 variants on this page


Untreated, early-stage favorable

Definitions of favorable/unfavorable risk factors vary somewhat across sites; see original sources for details.

ABVD

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ABVD: Adriamycin (Doxorubicin), Bleomycin, Vinblastine, Dacarbazine

Regimen

Study Evidence Comparator Efficacy
Raemaekers et al. 2014 (EORTC/LYSA/FIL H10) Phase III ABVD x 3 -> INRT Inconclusive whether noninferior
Radford et al. 2015 (UK NCRI RAPID) Phase III ABVD x 3 -> IFRT Inconclusive whether noninferior

4-week cycles, see note

Note: Patients in EORTC/LYSA/FIL H10 received 2 cycles of ABVD followed by interim PET-CT; those with a negative interim PET-CT (1 or 2 points on the 5-point Deauville scale) were randomized to receive 2 more cycles of ABVD versus 1 more cycle of ABVD followed by INRT 30 Gy (+ 6 Gy boost); those with a positive PET-CT proceeded to receive escalated BEACOPP followed by INRT 30 Gy (+ 6 Gy boost). Patients in UK NCRI RAPID received 3 cycles of ABVD followed by interim PET-CT; those with a negative PET-CT after the 3rd cycle (1 or 2 points on the 5-point Deauville scale) were randomized to receive IFRT versus no further treatment; those with a positive PET-CT proceeded to receive one more cycle of ABVD followed by IFRT.

References

  1. Raemaekers JM, André MP, Federico M, Girinsky T, Oumedaly R, Brusamolino E, Brice P, Fermé C, van der Maazen R, Gotti M, Bouabdallah R, Sebban CJ, Lievens Y, Re A, Stamatoullas A, Morschhauser F, Lugtenburg PJ, Abruzzese E, Olivier P, Casasnovas RO, van Imhoff G, Raveloarivahy T, Bellei M, van der Borght T, Bardet S, Versari A, Hutchings M, Meignan M, Fortpied C. Omitting radiotherapy in early positron emission tomography-negative stage I/II Hodgkin lymphoma is associated with an increased risk of early relapse: Clinical results of the preplanned interim analysis of the randomized EORTC/LYSA/FIL H10 trial. J Clin Oncol. 2014 Apr 20;32(12):1188-94. Epub 2014 Mar 17. link to original article contains protocol PubMed
  2. Radford J, Illidge T, Counsell N, Hancock B, Pettengell R, Johnson P, Wimperis J, Culligan D, Popova B, Smith P, McMillan A, Brownell A, Kruger A, Lister A, Hoskin P, O'Doherty M, Barrington S. Results of a trial of PET-directed therapy for early-stage Hodgkin's lymphoma. N Engl J Med. 2015 Apr 23;372(17):1598-607. link to original article contains protocol PubMed

ABVD -> RT

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ABVD: Adriamycin (Doxorubicin), Bleomycin, Vinblastine, Dacarbazine
RT: Radiation Therapy

Regimen

Study Evidence Comparator Efficacy
Bonadonna et al. 2004 Phase III ABVD x 4 -> IFRT
ABVD x 4 -> STNI
Raemaekers et al. 2014 (EORTC/LYSA/FIL H10) Phase III ABVD x 4 Inconclusive whether noninferior
Radford et al. 2015 (UK NCRI RAPID) Phase III ABVD x 3 Inconclusive whether noninferior

4-week cycles, see note:

Note: Patients in Bonadonna et al. 2004 received 4 cycles of ABVD followed by STNI versus IFRT. Patients in EORTC/LYSA/FIL H10 received 2 cycles of ABVD followed by interim PET-CT; those with a negative interim PET-CT (1 or 2 points on the 5-point Deauville scale) were randomized to receive 2 more cycles of ABVD versus 1 more cycle of ABVD followed by INRT 30 Gy (+ 6 Gy boost); those with a positive PET-CT proceeded to receive escalated BEACOPP followed by INRT 30 Gy (+ 6 Gy boost). Patients in UK NCRI RAPID received 3 cycles of ABVD followed by interim PET-CT; those with a negative PET-CT after the 3rd cycle (1 or 2 points on the 5-point Deauville scale) were randomized to receive IFRT versus no further treatment; those with a positive PET-CT proceeded to receive one more cycle of ABVD followed by IFRT.

References

  1. Bonadonna G, Bonfante V, Viviani S, Di Russo A, Villani F, Valagussa P. ABVD plus subtotal nodal versus involved-field radiotherapy in early-stage Hodgkin's disease: long-term results. J Clin Oncol. 2004 Jul 15;22(14):2835-41. link to original article contains protocol PubMed
  2. Radford J, Illidge T, Counsell N, Hancock B, Pettengell R, Johnson P, Wimperis J, Culligan D, Popova B, Smith P, McMillan A, Brownell A, Kruger A, Lister A, Hoskin P, O'Doherty M, Barrington S. Results of a trial of PET-directed therapy for early-stage Hodgkin's lymphoma. N Engl J Med. 2015 Apr 23;372(17):1598-607. link to original article contains protocol PubMed
  3. Raemaekers JM, André MP, Federico M, Girinsky T, Oumedaly R, Brusamolino E, Brice P, Fermé C, van der Maazen R, Gotti M, Bouabdallah R, Sebban CJ, Lievens Y, Re A, Stamatoullas A, Morschhauser F, Lugtenburg PJ, Abruzzese E, Olivier P, Casasnovas RO, van Imhoff G, Raveloarivahy T, Bellei M, van der Borght T, Bardet S, Versari A, Hutchings M, Meignan M, Fortpied C. Omitting radiotherapy in early positron emission tomography-negative stage I/II Hodgkin lymphoma is associated with an increased risk of early relapse: Clinical results of the preplanned interim analysis of the randomized EORTC/LYSA/FIL H10 trial. J Clin Oncol. 2014 Apr 20;32(12):1188-94. Epub 2014 Mar 17. link to original article contains protocol PubMed

Untreated, early-stage unfavorable

Definitions of favorable/unfavorable risk factors vary somewhat across sites; see original sources for details.

ABVD

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ABVD: Adriamycin (Doxorubicin), Bleomycin, Vinblastine, Dacarbazine

Regimen

Study Evidence Comparator Efficacy
Raemaekers et al. 2014 (EORTC/LYSA/FIL H10) Phase III ABVD x 4 -> INRT Inconclusive whether noninferior

4-week cycle x 2 cycles, then:

Patients with a negative interim PET-CT (1 or 2 points on the 5-point Deauville scale) were randomized to receive 4 more cycles of ABVD versus 2 more cycles of ABVD followed by INRT 30 Gy (+ 6 Gy boost). Patients with a positive PET-CT proceeded to receive escalated BEACOPP followed by INRT 30 Gy (+ 6 Gy boost).

References

  1. Raemaekers JM, André MP, Federico M, Girinsky T, Oumedaly R, Brusamolino E, Brice P, Fermé C, van der Maazen R, Gotti M, Bouabdallah R, Sebban CJ, Lievens Y, Re A, Stamatoullas A, Morschhauser F, Lugtenburg PJ, Abruzzese E, Olivier P, Casasnovas RO, van Imhoff G, Raveloarivahy T, Bellei M, van der Borght T, Bardet S, Versari A, Hutchings M, Meignan M, Fortpied C. Omitting radiotherapy in early positron emission tomography-negative stage I/II Hodgkin lymphoma is associated with an increased risk of early relapse: Clinical results of the preplanned interim analysis of the randomized EORTC/LYSA/FIL H10 trial. J Clin Oncol. 2014 Apr 20;32(12):1188-94. Epub 2014 Mar 17. link to original article contains protocol PubMed

ABVD -> RT

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ABVD: Adriamycin (Doxorubicin), Bleomycin, Vinblastine, Dacarbazine
RT: Radiation Therapy

Regimen

Study Evidence Comparator Efficacy
von Tresckow et al. 2012 (GHSG HD14) Phase III BEACOPPesc x 2 -> ABVD x 2 -> IFRT
Raemaekers et al. 2014 (EORTC/LYSA/FIL H10) Phase III ABVD x 6 Inconclusive whether noninferior
Behringer et al. 2014 (GHSG HD13) Phase III ABV -> IFRT
AV -> IFRT
AVD -> IFRT
Advani et al. 2015 (E2496) Phase III Stanford V -> RT Seems not superior

4-week cycles, see note

Note: Patients in GHSG HD14 received 4 cycles of ABVD followed by IFRT. Patients in EORTC/LYSA/FIL H10 received 2 cycles of ABVD followed by interim PET-CT; those with a negative interim PET-CT (1 or 2 points on the 5-point Deauville scale) were randomized to receive 4 more cycles of ABVD versus 2 more cycles of ABVD followed by INRT 30 Gy (+ 6 Gy boost); those with a positive PET-CT proceeded to receive escalated BEACOPP followed by INRT 30 Gy (+ 6 Gy boost). Patients in GHSG HD13 received 2 cycles of ABVD followed by 30 Gy involved-field radiotherapy (IFRT). Patients in E2496 received 6 to 8 cycles of ABVD; all patients received 36 Gy IFRT to the mediastinum, hila, and supraclavicular regions two to three weeks after completion of chemotherapy.

References

  1. von Tresckow B, Plütschow A, Fuchs M, Klimm B, Markova J, Lohri A, Kral Z, Greil R, Topp MS, Meissner J, Zijlstra JM, Soekler M, Stein H, Eich HT, Mueller RP, Diehl V, Borchmann P, Engert A. Dose-intensification in early unfavorable Hodgkin's lymphoma: final analysis of the German Hodgkin Study Group HD14 trial. J Clin Oncol. 2012 Mar 20;30(9):907-13. Epub 2012 Jan 23. link to original article contains verified protocol PubMed
  2. Raemaekers JM, André MP, Federico M, Girinsky T, Oumedaly R, Brusamolino E, Brice P, Fermé C, van der Maazen R, Gotti M, Bouabdallah R, Sebban CJ, Lievens Y, Re A, Stamatoullas A, Morschhauser F, Lugtenburg PJ, Abruzzese E, Olivier P, Casasnovas RO, van Imhoff G, Raveloarivahy T, Bellei M, van der Borght T, Bardet S, Versari A, Hutchings M, Meignan M, Fortpied C. Omitting radiotherapy in early positron emission tomography-negative stage I/II Hodgkin lymphoma is associated with an increased risk of early relapse: Clinical results of the preplanned interim analysis of the randomized EORTC/LYSA/FIL H10 trial. J Clin Oncol. 2014 Apr 20;32(12):1188-94. Epub 2014 Mar 17. link to original article contains protocol PubMed
  3. Behringer K, Goergen H, Hitz F, Zijlstra JM, Greil R, Markova J, Sasse S, Fuchs M, Topp MS, Soekler M, Mathas S, Meissner J, Wilhelm M, Koch P, Lindemann HW, Schalk E, Semrau R, Kriz J, Vieler T, Bentz M, Lange E, Mahlberg R, Hassler A, Vogelhuber M, Hahn D, Mezger J, Krause SW, Skoetz N, Böll B, von Tresckow B, Diehl V, Hallek M, Borchmann P, Stein H, Eich H, Engert A; German Hodgkin Study Group; Swiss Group for Clinical Cancer Research; Arbeitsgemeinschaft Medikamentöse Tumortherapie. Omission of dacarbazine or bleomycin, or both, from the ABVD regimen in treatment of early-stage favourable Hodgkin's lymphoma (GHSG HD13): an open-label, randomised, non-inferiority trial. Lancet. 2015 Apr 11;385(9976):1418-27. Epub 2014 Dec 22. Erratum in: Lancet. 2015 Apr 11;385(9976):1396. link to original article PubMed
  4. Advani RH, Hong F, Fisher RI, Bartlett NL, Robinson KS, Gascoyne RD, Wagner H Jr, Stiff PJ, Cheson BD, Stewart DA, Gordon LI, Kahl BS, Friedberg JW, Blum KA, Habermann TM, Tuscano JM, Hoppe RT, Horning SJ. Randomized Phase III Trial Comparing ABVD Plus Radiotherapy With the Stanford V Regimen in Patients With Stages I or II Locally Extensive, Bulky Mediastinal Hodgkin Lymphoma: A Subset Analysis of the North American Intergroup E2496 Trial. J Clin Oncol. 2015 Jun 10;33(17):1936-42. Epub 2015 Apr 20. link to original article contains limited protocol PubMed

BEACOPP, escalated -> ABVD -> RT

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BEACOPP: Bleomycin, Etoposide, Adriamycin (Doxorubicin), Cyclophosphamide, Oncovin (Vincristine), Procarbazine, Prednisone
ABVD: Adriamycin (Doxorubicin), Bleomycin, Vinblastine, Dacarbazine
RT: Radiation Therapy

Regimen

Study Evidence Comparator
von Tresckow et al. 2012 (GHSG HD14) Phase III ABVD x 4 -> IFRT

Escalated BEACOPP

Supportive medications:

  • Filgrastim (Neupogen) (dose not specified) SC once per day starting on day 8, continues until ANC > 1000/uL for 3 consecutive days

3-week cycle x 2 cycles, then:

ABVD

4-week cycle x 2 cycles

Treatment was followed by radiation therapy to the involved fields.

References

  1. von Tresckow B, Plütschow A, Fuchs M, Klimm B, Markova J, Lohri A, Kral Z, Greil R, Topp MS, Meissner J, Zijlstra JM, Soekler M, Stein H, Eich HT, Mueller RP, Diehl V, Borchmann P, Engert A. Dose-intensification in early unfavorable Hodgkin's lymphoma: final analysis of the German Hodgkin Study Group HD14 trial. J Clin Oncol. 2012 Mar 20;30(9):907-13. Epub 2012 Jan 23. link to original article contains verified protocol PubMed

Stanford V -> RT

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RT: Radiation Therapy

Regimen

Study Evidence Comparator Efficacy
Advani et al. 2015 (E2496) Phase III ABVD -> RT Seems not superior

In Advani et al. 2015 the Stanford V regimen is described as "once per week for 12 weeks." However, the regimen has previously been described as being 4-week cycles for 3 cycles (same duration, but schedule is different). Until this discrepancy is resolved, we replicate the 4-week cycle version here:

4-week cycle x 3 cycles

All patients received 36 Gy IFRT to the mediastinum, hila, and supraclavicular regions two to three weeks after completion of chemotherapy, with additional IFRT to additional sites ≥ 5 cm (details not described).

References

  1. Advani RH, Hong F, Fisher RI, Bartlett NL, Robinson KS, Gascoyne RD, Wagner H Jr, Stiff PJ, Cheson BD, Stewart DA, Gordon LI, Kahl BS, Friedberg JW, Blum KA, Habermann TM, Tuscano JM, Hoppe RT, Horning SJ. Randomized Phase III Trial Comparing ABVD Plus Radiotherapy With the Stanford V Regimen in Patients With Stages I or II Locally Extensive, Bulky Mediastinal Hodgkin Lymphoma: A Subset Analysis of the North American Intergroup E2496 Trial. J Clin Oncol. 2015 Jun 10;33(17):1936-42. Epub 2015 Apr 20. link to original article contains limited protocol PubMed

Untreated, advanced stage

Generally defined as stage III/IV or stage II with bulky disease. Definitions for bulky disease vary across sites; see original sources for details,

ABVD

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ABVD: Adriamycin (Doxorubicin), Bleomycin, Vinblastine, Dacarbazine

Regimen

Study Evidence Comparator Efficacy
Santoro et al. 1987 Phase III MOPP
Canellos et al. 1992 Phase III MOPP; MOPP/ABVD
Hoskin et al. 2009 (UK NCRI ISRCTN 64141244) Phase III Stanford V Seems not superior
Viviani et al. 2011 Phase III Escalated BEACOPP -> BEACOPP Seems to have inferior FFFP
Gordon et al. 2013 (E2496) Phase III Stanford V Seems not superior
Mounier et al. 2014 (LYSA H34) Phase III Escalated BEACOPP -> BEACOPP Might have inferior EFS

4-week cycle x 8 cycles

References

  1. Santoro A, Bonadonna G, Valagussa P, Zucali R, Viviani S, Villani F, Pagnoni AM, Bonfante V, Musumeci R, Crippa F, et al. Long-term results of combined chemotherapy-radiotherapy approach in Hodgkin's disease: superiority of ABVD plus radiotherapy versus MOPP plus radiotherapy. J Clin Oncol. 1987 Jan;5(1):27-37. link to original article PubMed
  2. Canellos GP, Anderson JR, Propert KJ, Nissen N, Cooper MR, Henderson ES, Green MR, Gottlieb A, Peterson BA. Chemotherapy of advanced Hodgkin's disease with MOPP, ABVD, or MOPP alternating with ABVD. N Engl J Med. 1992 Nov 19;327(21):1478-84. link to original article PubMed
  3. Hoskin PJ, Lowry L, Horwich A, Jack A, Mead B, Hancock BW, Smith P, Qian W, Patrick P, Popova B, Pettitt A, Cunningham D, Pettengell R, Sweetenham J, Linch D, Johnson PW. Randomized comparison of the stanford V regimen and ABVD in the treatment of advanced Hodgkin's Lymphoma: United Kingdom National Cancer Research Institute Lymphoma Group Study ISRCTN 64141244. J Clin Oncol. 2009 Nov 10;27(32):5390-6. Epub 2009 Sep 8. link to original article PubMed
  4. Viviani S, Zinzani PL, Rambaldi A, Brusamolino E, Levis A, Bonfante V, Vitolo U, Pulsoni A, Liberati AM, Specchia G, Valagussa P, Rossi A, Zaja F, Pogliani EM, Pregno P, Gotti M, Gallamini A, Rota Scalabrini D, Bonadonna G, Gianni AM; Michelangelo Foundation; Gruppo Italiano di Terapie Innovative nei Linfomi; Intergruppo Italiano Linfomi. ABVD versus BEACOPP for Hodgkin's lymphoma when high-dose salvage is planned. N Engl J Med. 2011 Jul 21;365(3):203-12. link to original article contains verified protocol PubMed
  5. Gordon LI, Hong F, Fisher RI, Bartlett NL, Connors JM, Gascoyne RD, Wagner H, Stiff PJ, Cheson BD, Gospodarowicz M, Advani R, Kahl BS, Friedberg JW, Blum KA, Habermann TM, Tuscano JM, Hoppe RT, Horning SJ. Randomized Phase III Trial of ABVD Versus Stanford V With or Without Radiation Therapy in Locally Extensive and Advanced-Stage Hodgkin Lymphoma: An Intergroup Study Coordinated by the Eastern Cooperative Oncology Group (E2496). J Clin Oncol. 2013 Feb 20;31(6):684-91. Epub 2012 Nov 26. link to original article PubMed
  6. Mounier N, Brice P, Bologna S, Briere J, Gaillard I, Heczko M, Gabarre J, Casasnovas O, Jaubert J, Colin P, Delmer A, Devidas A, Bachy E, Nicolas-Virelizier E, Aoudjhane A, Humbrecht C, Andre M, Carde P; Lymphoma Study Association (LYSA). ABVD (8 cycles) versus BEACOPP (4 escalated cycles =4 baseline): final results in stage III-IV low-risk Hodgkin lymphoma (IPS 0-2) of the LYSA H34 randomized trial. Ann Oncol. 2014 Aug;25(8):1622-8. Epub 2014 May 14. link to original article contains verified protocol PubMed

ABVD, DD-DI

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ABVD, DD-DI: Adriamycin (Doxorubicin), Bleomycin, Vinblastine, Dacarbazine, Dose-Dense and Dose-Intense

Regimen

Study Evidence
Russo et al. 2014 Phase II

Supportive medications:

21-day cycle x 6 cycles

References

  1. Russo F, Corazzelli G, Frigeri F, Capobianco G, Aloj L, Volzone F, De Chiara A, Bonelli A, Gatani T, Marcacci G, Donnarumma D, Becchimanzi C, de Lutio E, Ionna F, De Filippi R, Lastoria S, Pinto A. A phase II study of dose-dense and dose-intense ABVD (ABVD(DD-DI) ) without consolidation radiotherapy in patients with advanced Hodgkin lymphoma. Br J Haematol. 2014 Jul;166(1):118-29. Epub 2014 Mar 27. link to original article contains verified protocol PubMed

BEACOPP

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BEACOPP: Bleomycin, Etoposide, Adriamycin (Doxorubicin), Cyclophosphamide, Oncovin (Vincristine), Procarbazine, Prednisone

Regimen

Study Evidence Comparator Efficacy
Diehl et al. 1997 Non-randomized
Diehl et al. 1998 (GHSG HD9) Phase III Escalated dose BEACOPP Inferior FFTF
Diehl et al. 1998 (GHSG HD9) Phase III COPP-ABVD Seems to have superior FFTF
Ballova et al. 2005 (GHSG HD9elderly) Phase III COPP-ABVD Seems not superior

Note that this is technically "BEACOPP II." The original "BEACOPP I" is detailed in Diehl et al. 1997 but is of historical interest, only.

3-week cycle x 8 cycles

References

  1. Diehl V, Sieber M, Rüffer U, Lathan B, Hasenclever D, Pfreundschuh M, Loeffler M, Lieberz D, Koch P, Adler M, Tesch H. BEACOPP: an intensified chemotherapy regimen in advanced Hodgkin's disease. The German Hodgkin's Lymphoma Study Group. Ann Oncol. 1997 Feb;8(2):143-8. link to original article contains verified protocol PubMed
  2. Diehl V, Franklin J, Hasenclever D, Tesch H, Pfreundschuh M, Lathan B, Paulus U, Sieber M, Rueffer JU, Sextro M, Engert A, Wolf J, Hermann R, Holmer L, Stappert-Jahn U, Winnerlein-Trump E, Wulf G, Krause S, Glunz A, von Kalle K, Bischoff H, Haedicke C, Duehmke E, Georgii A, Loeffler M. BEACOPP, a new dose-escalated and accelerated regimen, is at least as effective as COPP/ABVD in patients with advanced-stage Hodgkin's lymphoma: interim report from a trial of the German Hodgkin's Lymphoma Study Group. J Clin Oncol. 1998 Dec;16(12):3810-21. link to original articlecontains verified protocol PubMed
    1. Update: Diehl V, Franklin J, Pfreundschuh M, Lathan B, Paulus U, Hasenclever D, Tesch H, Herrmann R, Dörken B, Müller-Hermelink HK, Dühmke E, Loeffler M; German Hodgkin's Lymphoma Study Group. Standard and increased-dose BEACOPP chemotherapy compared with COPP-ABVD for advanced Hodgkin's disease. N Engl J Med. 2003 Jun 12;348(24):2386-95. link to original articlecontains protocol PubMed
  3. Ballova V, Rüffer JU, Haverkamp H, Pfistner B, Müller-Hermelink HK, Dühmke E, Worst P, Wilhelmy M, Naumann R, Hentrich M, Eich HT, Josting A, Löffler M, Diehl V, Engert A. A prospectively randomized trial carried out by the German Hodgkin Study Group (GHSG) for elderly patients with advanced Hodgkin's disease comparing BEACOPP baseline and COPP-ABVD (study HD9elderly). Ann Oncol. 2005 Jan;16(1):124-31. link to original articlecontains protocol PubMed

BEACOPP-14

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BEACOPP-14: Bleomycin, Etoposide, Adriamycin (Doxorubicin), Cyclophosphamide, Oncovin (Vincristine), Procarbazine, Prednisone, 14-day course

Regimen

Study Evidence Comparator
Sieber et al. 2003 Phase II
Engert et al. 2012 (GHSG HD15) Phase III Escalated BEACOPP x 8; Escalated BEACOPP x 6

Supportive medications:

  • Filgrastim (Neupogen) as follows:
    • <75 kg body weight: 300 mcg SC once per day on days 8 to 13
    • ≥75 kg body weight: 480 mcg SC once per day on days 8 to 13

2-week cycle x 8 cycles

References

  1. Sieber M, Bredenfeld H, Josting A, Reineke T, Rueffer U, Koch T, Naumann R, Boissevain F, Koch P, Worst P, Soekler M, Eich H, Müller-Hermelink HK, Franklin J, Paulus U, Wolf J, Engert A, Diehl V; German Hodgkin's Lymphoma Study Group. 14-day variant of the bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone regimen in advanced-stage Hodgkin's lymphoma: results of a pilot study of the German Hodgkin's Lymphoma Study Group. J Clin Oncol. 2003 May 1;21(9):1734-9. link to original article contains verified protocol PubMed
  2. Engert A, Haverkamp H, Kobe C, Markova J, Renner C, Ho A, Zijlstra J, Král Z, Fuchs M, Hallek M, Kanz L, Döhner H, Dörken B, Engel N, Topp M, Klutmann S, Amthauer H, Bockisch A, Kluge R, Kratochwil C, Schober O, Greil R, Andreesen R, Kneba M, Pfreundschuh M, Stein H, Eich HT, Müller RP, Dietlein M, Borchmann P, Diehl V; German Hodgkin Study Group; Swiss Group for Clinical Cancer Research; Arbeitsgemeinschaft Medikamentöse Tumortherapie. Reduced-intensity chemotherapy and PET-guided radiotherapy in patients with advanced stage Hodgkin's lymphoma (HD15 trial): a randomised, open-label, phase 3 non-inferiority trial. Lancet. 2012 May 12;379(9828):1791-9. Epub 2012 Apr 4. Erratum in: Lancet. 2012 May 12;379(9828):1790. link to original article PubMed

BEACOPP, escalated -> BEACOPP

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BEACOPP: Bleomycin, Etoposide, Adriamycin (Doxorubicin), Cyclophosphamide, Oncovin (Vincristine), Procarbazine, Prednisone

Regimen

Study Evidence Comparator
Diehl et al. 1998 (GHSG HD9) Phase III ABVD
Viviani et al. 2011 Phase III ABVD
Borchmann et al. 2011 (GHSG HD12) Phase III Escalated BEACOPP
Mounier et al. 2014 (LYSA H34) Phase III ABVD

Escalated phase

Supportive medications:

  • Filgrastim (Neupogen) 300 mcg SC once per day starting day 8, continues until ANC > 1000/uL for 3 consecutive days (Viviani et al. 2011) or until day 14 (Mounier et al. 2014)

3-week cycle x 4 cycles

Standard phase

Supportive medications:

  • Filgrastim (Neupogen) 300 mcg SC once per day starting day 8, continues until ANC > 1000/uL for 3 consecutive days (Viviani et al. 2011) or until day 14 (Mounier et al. 2014)

3-week cycle x 4 cycles

References

  1. Diehl V, Franklin J, Hasenclever D, Tesch H, Pfreundschuh M, Lathan B, Paulus U, Sieber M, Rueffer JU, Sextro M, Engert A, Wolf J, Hermann R, Holmer L, Stappert-Jahn U, Winnerlein-Trump E, Wulf G, Krause S, Glunz A, von Kalle K, Bischoff H, Haedicke C, Duehmke E, Georgii A, Loeffler M. BEACOPP, a new dose-escalated and accelerated regimen, is at least as effective as COPP/ABVD in patients with advanced-stage Hodgkin's lymphoma: interim report from a trial of the German Hodgkin's Lymphoma Study Group. J Clin Oncol. 1998 Dec;16(12):3810-21. link to original articlecontains verified protocol PubMed
    1. Update: Diehl V, Franklin J, Pfreundschuh M, Lathan B, Paulus U, Hasenclever D, Tesch H, Herrmann R, Dörken B, Müller-Hermelink HK, Dühmke E, Loeffler M; German Hodgkin's Lymphoma Study Group. Standard and increased-dose BEACOPP chemotherapy compared with COPP-ABVD for advanced Hodgkin's disease. N Engl J Med. 2003 Jun 12;348(24):2386-95. link to original articlecontains protocol PubMed
    2. Update: Engert A, Diehl V, Franklin J, Lohri A, Dörken B, Ludwig WD, Koch P, Hänel M, Pfreundschuh M, Wilhelm M, Trümper L, Aulitzky WE, Bentz M, Rummel M, Sezer O, Müller-Hermelink HK, Hasenclever D, Löffler M. Escalated-dose BEACOPP in the treatment of patients with advanced-stage Hodgkin's lymphoma: 10 years of follow-up of the GHSG HD9 study. J Clin Oncol. 2009 Sep 20;27(27):4548-54. link to original article PubMed
  2. Viviani S, Zinzani PL, Rambaldi A, Brusamolino E, Levis A, Bonfante V, Vitolo U, Pulsoni A, Liberati AM, Specchia G, Valagussa P, Rossi A, Zaja F, Pogliani EM, Pregno P, Gotti M, Gallamini A, Rota Scalabrini D, Bonadonna G, Gianni AM; Michelangelo Foundation; Gruppo Italiano di Terapie Innovative nei Linfomi; Intergruppo Italiano Linfomi. ABVD versus BEACOPP for Hodgkin's lymphoma when high-dose salvage is planned. N Engl J Med. 2011 Jul 21;365(3):203-12. link to original article contains verified protocol PubMed
  3. Borchmann P, Haverkamp H, Diehl V, Cerny T, Markova J, Ho AD, Eich HT, Mueller-Hermelink HK, Kanz L, Greil R, Rank A, Paulus U, Smardova L, Huber C, Dörken B, Nerl C, Krause SW, Mueller RP, Fuchs M, Engert A. Eight cycles of escalated-dose BEACOPP compared with four cycles of escalated-dose BEACOPP followed by four cycles of baseline-dose BEACOPP with or without radiotherapy in patients with advanced-stage hodgkin's lymphoma: final analysis of the HD12 trial of the German Hodgkin Study Group. J Clin Oncol. 2011 Nov 10;29(32):4234-42. Epub 2011 Oct 11. link to original article PubMed
  4. Mounier N, Brice P, Bologna S, Briere J, Gaillard I, Heczko M, Gabarre J, Casasnovas O, Jaubert J, Colin P, Delmer A, Devidas A, Bachy E, Nicolas-Virelizier E, Aoudjhane A, Humbrecht C, Andre M, Carde P; Lymphoma Study Association (LYSA). ABVD (8 cycles) versus BEACOPP (4 escalated cycles =4 baseline): final results in stage III-IV low-risk Hodgkin lymphoma (IPS 0-2) of the LYSA H34 randomized trial. Ann Oncol. 2014 Aug;25(8):1622-8. Epub 2014 May 14. link to original article contains verified protocol PubMed

BEACOPP, escalated dose

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BEACOPP: Bleomycin, Etoposide, Adriamycin (Doxorubicin), Cyclophosphamide, Oncovin (Vincristine), Procarbazine, Prednisone

Regimen #1

Study Evidence Comparator
Engert et al. 2012 (GHSG HD15) Phase III BEACOPP-14; Escalated BEACOPP x 8

Details are not available in the abstract; it is assumed that the regimen is identical to escalated BEACOPP x 8, with 2 fewer cycles.

3-week cycle x 6 cycles

Regimen #2

Study Evidence Comparator
Diehl et al. 1998 (GHSG HD9) Phase III BEACOPP
Diehl et al. 1998 (GHSG HD9) Phase III COPP-ABVD
Borchmann et al. 2011 (GHSG HD12) Phase III Escalated BEACOPP -> BEACOPP
Engert et al. 2012 (GHSG HD15) Phase III BEACOPP-14; Escalated BEACOPP x 6

3-week cycle x 8 cycles

References

  1. Diehl V, Franklin J, Hasenclever D, Tesch H, Pfreundschuh M, Lathan B, Paulus U, Sieber M, Rueffer JU, Sextro M, Engert A, Wolf J, Hermann R, Holmer L, Stappert-Jahn U, Winnerlein-Trump E, Wulf G, Krause S, Glunz A, von Kalle K, Bischoff H, Haedicke C, Duehmke E, Georgii A, Loeffler M. BEACOPP, a new dose-escalated and accelerated regimen, is at least as effective as COPP/ABVD in patients with advanced-stage Hodgkin's lymphoma: interim report from a trial of the German Hodgkin's Lymphoma Study Group. J Clin Oncol. 1998 Dec;16(12):3810-21. link to original articlecontains verified protocol PubMed
    1. Update: Diehl V, Franklin J, Pfreundschuh M, Lathan B, Paulus U, Hasenclever D, Tesch H, Herrmann R, Dörken B, Müller-Hermelink HK, Dühmke E, Loeffler M; German Hodgkin's Lymphoma Study Group. Standard and increased-dose BEACOPP chemotherapy compared with COPP-ABVD for advanced Hodgkin's disease. N Engl J Med. 2003 Jun 12;348(24):2386-95. link to original articlecontains protocol PubMed
    2. Update: Engert A, Diehl V, Franklin J, Lohri A, Dörken B, Ludwig WD, Koch P, Hänel M, Pfreundschuh M, Wilhelm M, Trümper L, Aulitzky WE, Bentz M, Rummel M, Sezer O, Müller-Hermelink HK, Hasenclever D, Löffler M. Escalated-dose BEACOPP in the treatment of patients with advanced-stage Hodgkin's lymphoma: 10 years of follow-up of the GHSG HD9 study. J Clin Oncol. 2009 Sep 20;27(27):4548-54. link to original article PubMed
  2. Borchmann P, Haverkamp H, Diehl V, Cerny T, Markova J, Ho AD, Eich HT, Mueller-Hermelink HK, Kanz L, Greil R, Rank A, Paulus U, Smardova L, Huber C, Dörken B, Nerl C, Krause SW, Mueller RP, Fuchs M, Engert A. Eight cycles of escalated-dose BEACOPP compared with four cycles of escalated-dose BEACOPP followed by four cycles of baseline-dose BEACOPP with or without radiotherapy in patients with advanced-stage hodgkin's lymphoma: final analysis of the HD12 trial of the German Hodgkin Study Group. J Clin Oncol. 2011 Nov 10;29(32):4234-42. Epub 2011 Oct 11. link to original article PubMed
  3. Engert A, Haverkamp H, Kobe C, Markova J, Renner C, Ho A, Zijlstra J, Král Z, Fuchs M, Hallek M, Kanz L, Döhner H, Dörken B, Engel N, Topp M, Klutmann S, Amthauer H, Bockisch A, Kluge R, Kratochwil C, Schober O, Greil R, Andreesen R, Kneba M, Pfreundschuh M, Stein H, Eich HT, Müller RP, Dietlein M, Borchmann P, Diehl V; German Hodgkin Study Group; Swiss Group for Clinical Cancer Research; Arbeitsgemeinschaft Medikamentöse Tumortherapie. Reduced-intensity chemotherapy and PET-guided radiotherapy in patients with advanced stage Hodgkin's lymphoma (HD15 trial): a randomised, open-label, phase 3 non-inferiority trial. Lancet. 2012 May 12;379(9828):1791-9. Epub 2012 Apr 4. Erratum in: Lancet. 2012 May 12;379(9828):1790. link to original article PubMed

C-MOPP/ABV

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C-MOPP: CyclophosphaMide, Oncovin (Vincristine), Procarbazine, Prednisone
ABV: Adriamycin (Doxorubicin), Bleomycin, Vinblastine

Regimen

Study Evidence
Montoto et al. 2000 Phase II

Q28days x 8 cycles

  • 25 to 40 Gy of radiation therapy given over extended fields (mantle or inverted "Y" type) to patients with bulky disease or ones with residual disease after completion of chemotherapy

References

  1. Montoto S, Camós M, López-Guillermo A, Bosch F, Cervantes F, Blandé J, Esteve J, Cobo F, Nomdedeu B, Campo E, Montserrat E. Hybrid chemotherapy consisting of cyclophosphamide, vincristine, procarbazine, prednisone, doxorubicin, bleomycin, and vinblastine (C-MOPP/ABV) as first-line treatment for patients with advanced Hodgkin disease. Cancer. 2000 May 1;88(9):2142-8. link to original article contains protocol PubMed]

COPP-ABVD, C-MOPP/ABVD

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COPP: Cyclophosphamide, Oncovin (Vincristine), Procarbazine, Prednisone
C-MOPP: CyclophosphaMide, Oncovin (Vincristine), Procarbazine, Prednisone
ABVD: Adriamycin (Doxorubicin), Bleomycin, Vinblastine, Dacarbazine

Regimen

Study Evidence Comparator
Diehl et al. 1998 (GHSG HD9) Phase III Escalated BEACOPP -> BEACOPP
Takenaka et al. 2000 (JCOG 8905) Phase II
Ballova et al. 2005 (GHSG HD9elderly) Phase III BEACOPP

COPP

4-week cycle x 5 total cycles of C-MOPP, alternating with 5 total cycles of ABVD

ABVD

4-week cycle x 5 total cycles of ABVD, alternating with 5 total cycles of C-MOPP

  • 30 Gy of involved field radiation after completion of chemotherapy was given to patients with bulky (=10 cm maximum diameter) disease

Delayed treatment and discontinuations:

  • Treatment was postponed for at least 1 week or until recovery if:
    • Pretreatment ANC was <1500
    • Platelet count was <100 x 10^3
    • AST/S-GOT was >100 IU/L
    • Total bilirubin was >2
  • Vincristine (Oncovin) and Vinblastine (Velban) were temporarily discontinued if patients had grade 2 or greater neurotoxicity (e.g. motor weakness, paresthesia, constipation)
  • Doxorubicin (Adriamycin) was discontinued if cardiac LV ejection fraction was <50%
  • Bleomycin (Blenoxane) was stopped if the PaO2 was less than 70 mmHg or if it decreased more than 10 mmHg from the previous measurement
  • Note: Dacarbazine (DTIC) 250 mg/m2 was used at this dose reduction based on experiences in a pilot study in which there was severe emesis with Dacarbazine (DTIC) 375 mg/m2.

References

  1. Diehl V, Franklin J, Hasenclever D, Tesch H, Pfreundschuh M, Lathan B, Paulus U, Sieber M, Rueffer JU, Sextro M, Engert A, Wolf J, Hermann R, Holmer L, Stappert-Jahn U, Winnerlein-Trump E, Wulf G, Krause S, Glunz A, von Kalle K, Bischoff H, Haedicke C, Duehmke E, Georgii A, Loeffler M. BEACOPP, a new dose-escalated and accelerated regimen, is at least as effective as COPP/ABVD in patients with advanced-stage Hodgkin's lymphoma: interim report from a trial of the German Hodgkin's Lymphoma Study Group. J Clin Oncol. 1998 Dec;16(12):3810-21. link to original articlecontains verified protocol PubMed
    1. Update: Diehl V, Franklin J, Pfreundschuh M, Lathan B, Paulus U, Hasenclever D, Tesch H, Herrmann R, Dörken B, Müller-Hermelink HK, Dühmke E, Loeffler M; German Hodgkin's Lymphoma Study Group. Standard and increased-dose BEACOPP chemotherapy compared with COPP-ABVD for advanced Hodgkin's disease. N Engl J Med. 2003 Jun 12;348(24):2386-95. link to original articlecontains protocol PubMed
  2. Takenaka T, Mikuni C, Miura A, Sasaki T, Suzuki H, Hotta T, Hirano M, Fukuhara S, Sugiyama H, Nasu K, Dohi H, Kozuru M, Tomonaga M, Tajima K, Niimi M, Fukuda H, Mukai K, Shimoyama M. Alternating combination chemotherapy C-MOPP (cyclophosphamide, vincristine, procarbazine, prednisone) and ABVd (adriamycin, bleomycin, vinblastine, dacarbazine) in clinical stage II-IV Hodgkin's disease: a multicenter phase II study (JCOG 8905). The Lymphoma Study Group of the Japan Clinical Oncology Group. Jpn J Clin Oncol. 2000 Mar;30(3):146-52. link to original article contains protocol PubMed
  3. Ballova V, Rüffer JU, Haverkamp H, Pfistner B, Müller-Hermelink HK, Dühmke E, Worst P, Wilhelmy M, Naumann R, Hentrich M, Eich HT, Josting A, Löffler M, Diehl V, Engert A. A prospectively randomized trial carried out by the German Hodgkin Study Group (GHSG) for elderly patients with advanced Hodgkin's disease comparing BEACOPP baseline and COPP-ABVD (study HD9elderly). Ann Oncol. 2005 Jan;16(1):124-31. link to original articlecontains protocol PubMed

MOPP

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MOPP: Mechlorethamine, Oncovin (Vincristine), Procarbazine, Prednisone

Regimen

Study Evidence Comparator
Devita et al. 1970 Phase II
Bonadonna et al. 1975 Phase III ABVD
Cooper et al. 1980 Phase III CVPP
MVPP
Santoro et al. 1982 Phase III MOPP/ABVD
Santoro et al. 1987 Phase III ABVD
Canellos et al. 1992 Phase III ABVD
MOPP/ABVD

4-week cycle x 6 cycles

References

  1. Devita VT Jr, Serpick AA, Carbone PP. Combination chemotherapy in the treatment of advanced Hodgkin's disease. Ann Intern Med. 1970 Dec;73(6):881-95. link to original article contains protocol PubMed content property of HemOnc.org
  2. Bonadonna G, Zucali R, Monfardini S, De Lena M, Uslenghi C. Combination chemotherapy of Hodgkin's disease with adriamycin, bleomycin, vinblastine, and imidazole carboxamide versus MOPP. Cancer. 1975 Jul;36(1):252-9. link to original article PubMed
  3. Cooper MR, Pajak TF, Nissen NI, Stutzman L, Brunner K, Cuttner J, Falkson G, Grunwald H, Bank A, Leone L, Seligman BR, Silver RT, Weiss RB, Haurani F, Blom J, Spurr CL, Glidewell OJ, Gottlieb AJ, Holland JF. A new effective four-drug combination of CCNU (1-[2-chloroethyl]-3-cyclohexyl-1-nitrosourea) (NSC-79038), vinblastine, prednisone, and procarbazine for the treatment of advanced Hodgkin's disease. Cancer. 1980 Aug 15;46(4):654-62. link to original article PubMed
  4. Santoro A, Bonadonna G, Bonfante V, Valagussa P. Alternating drug combinations in the treatment of advanced Hodgkin's disease. N Engl J Med. 1982 Apr 1;306(13):770-5. link to original article PubMed
    1. Update: Bonadonna G, Valagussa P, Santoro A. Alternating non-cross-resistant combination chemotherapy or MOPP in stage IV Hodgkin's disease. A report of 8-year results. Ann Intern Med. 1986 Jun;104(6):739-46. link to original article PubMed
  5. Santoro A, Bonadonna G, Valagussa P, Zucali R, Viviani S, Villani F, Pagnoni AM, Bonfante V, Musumeci R, Crippa F, et al. Long-term results of combined chemotherapy-radiotherapy approach in Hodgkin's disease: superiority of ABVD plus radiotherapy versus MOPP plus radiotherapy. J Clin Oncol. 1987 Jan;5(1):27-37. link to original article PubMed
  6. Canellos GP, Anderson JR, Propert KJ, Nissen N, Cooper MR, Henderson ES, Green MR, Gottlieb A, Peterson BA. Chemotherapy of advanced Hodgkin's disease with MOPP, ABVD, or MOPP alternating with ABVD. N Engl J Med. 1992 Nov 19;327(21):1478-84. link to original article PubMed

MOPP/ABVD

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MOPP: Mustargen (Mechlorethamine), Oncovin (Vincristine), Procarbazine, Prednisone
ABVD: Adriamycin (Doxorubicin), Bleomycin, Vinblastine, Dacarbazine

Regimen

To be completed

References

  1. Santoro A, Bonadonna G, Bonfante V, Valagussa P. Alternating drug combinations in the treatment of advanced Hodgkin's disease. N Engl J Med. 1982 Apr 1;306(13):770-5. link to original article PubMed
    1. Update: Bonadonna G, Valagussa P, Santoro A. Alternating non-cross-resistant combination chemotherapy or MOPP in stage IV Hodgkin's disease. A report of 8-year results. Ann Intern Med. 1986 Jun;104(6):739-46. link to original article PubMed
  2. Canellos GP, Anderson JR, Propert KJ, Nissen N, Cooper MR, Henderson ES, Green MR, Gottlieb A, Peterson BA. Chemotherapy of advanced Hodgkin's disease with MOPP, ABVD, or MOPP alternating with ABVD. N Engl J Med. 1992 Nov 19;327(21):1478-84. link to original article PubMed
  3. Somers R, Carde P, Henry-Amar M, Tarayre M, Thomas J, Hagenbeek A, Monconduit M, de Pauw BE, Breed WP, Verdonck L, et al. A randomized study in stage IIIB and IV Hodgkin's disease comparing eight courses of MOPP versus an alteration of MOPP with ABVD: a European Organization for Research and Treatment of Cancer Lymphoma Cooperative Group and Groupe Pierre-et-Marie-Curie controlled clinical trial. J Clin Oncol. 1994 Feb;12(2):279-87. link to original article PubMed
  4. Salvagno L, Sorarù M, Sotti G, Aversa S, Chiarion Sileni V, Mazzarotto R, Scarzello G, Bianco A, Pappagallo GL, Fiorentino MV. Hybrid MOPP/ABVD and radiotherapy in advanced Hodgkin's disease. Ann Oncol. 1995 Feb;6(2):173-9. link to original article PubMed
  5. Viviani S, Bonadonna G, Santoro A, Bonfante V, Zanini M, Devizzi L, Soncini F, Valagussa P. Alternating versus hybrid MOPP and ABVD combinations in advanced Hodgkin's disease: ten-year results. J Clin Oncol. 1996 May;14(5):1421-30. link to original article PubMed
  6. Connors JM, Klimo P, Adams G, Burns BF, Cooper I, Meyer RM, O'Reilly SE, Pater J, Quirt I, Sadura A, Shustik C, Skillings J, Sutcliffe S, Verma S, Yoshida S, Zee B. Treatment of advanced Hodgkin's disease with chemotherapy--comparison of MOPP/ABV hybrid regimen with alternating courses of MOPP and ABVD: a report from the National Cancer Institute of Canada clinical trials group. J Clin Oncol. 1997 Apr;15(4):1638-45. Erratum in: J Clin Oncol 1997 Jul;15(7):2762. link to original article PubMed
  7. Longo DL, Glatstein E, Duffey PL, Young RC, Ihde DC, Bastian AW, Wilson WH, Wittes RE, Jaffe ES, Hubbard SM, DeVita VT Jr. Alternating MOPP and ABVD chemotherapy plus mantle-field radiation therapy in patients with massive mediastinal Hodgkin's disease. J Clin Oncol. 1997 Nov;15(11):3338-46. link to original article PubMed

Stanford V

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Regimen

Study Evidence Comparator Efficacy
Hoskin et al. 2009 (UK NCRI ISRCTN 64141244) Phase III ABVD Seems not superior
Gordon et al. 2013 (E2496) Phase III ABVD Seems not superior

Supportive medications:

  • If dose reduction or delay occurred at any time during chemotherapy, Filgrastim (Neupogen) 5 mcg/kg SC once per day x 5 days (starting 48 hours after myelosuppressive chemotherapy) should be given after all subsequent day 1 and 15 doses of chemotherapy. It was not precisely specified when to discontinue Filgrastim (Neupogen).
  • Ranitidine (Zantac) 150 mg PO BID throughout the course of treatment
  • Trimethoprim/Sulfamethoxazole (Bactrim DS) (160/800 mg) PO BID throughout the course of treatment
  • Acyclovir (Zovirax) 200 mg PO TID throughout the course of treatment
  • Ketoconazole (Nizoral) 200 mg PO once per day throughout the course of treatment; note: this may be optional--Horning SJ et al. J Clin Oncol (2000) listed this as a prophylactic medication, but Horning SJ et al. J Clin Oncol (2002) did not list this when prophylactic medications were specifically listed.

4-week cycle x 3 cycles

  • 36 Gy of consolidative radiation (1.8 Gy in 20 fractions) is started 2 to 4 weeks after chemotherapy is complete and is given to sites of disease = 5 cm and/or to macroscopic nodules in the spleen.

Dose reductions and delayed treatment:

References

  1. Horning SJ, Williams J, Bartlett NL, Bennett JM, Hoppe RT, Neuberg D, Cassileth P. Assessment of the Stanford V regimen and consolidative radiotherapy for bulky and advanced Hodgkin's disease: Eastern Cooperative Oncology Group pilot study E1492. J Clin Oncol. 2000 Mar;18(5):972-80. link to original article contains protocol PubMed
  2. Horning SJ, Hoppe RT, Breslin S, Bartlett NL, Brown BW, Rosenberg SA. Stanford V and radiotherapy for locally extensive and advanced Hodgkin's disease: mature results of a prospective clinical trial. J Clin Oncol. 2002 Feb 1;20(3):630-7. link to original article contains protocol PubMed
  3. Hoskin PJ, Lowry L, Horwich A, Jack A, Mead B, Hancock BW, Smith P, Qian W, Patrick P, Popova B, Pettitt A, Cunningham D, Pettengell R, Sweetenham J, Linch D, Johnson PW. Randomized comparison of the stanford V regimen and ABVD in the treatment of advanced Hodgkin's Lymphoma: United Kingdom National Cancer Research Institute Lymphoma Group Study ISRCTN 64141244. J Clin Oncol. 2009 Nov 10;27(32):5390-6. Epub 2009 Sep 8. link to original article PubMed
  4. Edwards-Bennett SM, Jacks LM, Moskowitz CH, Wu EJ, Zhang Z, Noy A, Portlock CS, Straus DJ, Zelenetz AD, Yahalom J. Stanford V program for locally extensive and advanced Hodgkin lymphoma: the Memorial Sloan-Kettering Cancer Center experience. Ann Oncol. 2010 Mar;21(3):574-81. link to original article PubMed
  5. Gordon LI, Hong F, Fisher RI, Bartlett NL, Connors JM, Gascoyne RD, Wagner H, Stiff PJ, Cheson BD, Gospodarowicz M, Advani R, Kahl BS, Friedberg JW, Blum KA, Habermann TM, Tuscano JM, Hoppe RT, Horning SJ. Randomized Phase III Trial of ABVD Versus Stanford V With or Without Radiation Therapy in Locally Extensive and Advanced-Stage Hodgkin Lymphoma: An Intergroup Study Coordinated by the Eastern Cooperative Oncology Group (E2496). J Clin Oncol. 2013 Feb 20;31(6):684-91. Epub 2012 Nov 26. link to original article PubMed

VEBEP

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VEBEP: Vepesid (Etoposide), Epirubicin, Bleomycin, Endoxan (Cyclophosphamide), Prednisolone

Regimen

Study Evidence
Viviani et al. 1999 Phase II

To be completed?

References

  1. Viviani S, Bonfante V, Santoro A, Zanini M, Devizzi L, Di Russo AD, Soncini F, Villani F, Ragni G, Valagussa P, Bonadonna G. Long-term results of an intensive regimen: VEBEP plus involved-field radiotherapy in advanced Hodgkin's disease. Cancer J Sci Am. 1999 Sep-Oct;5(5):275-82. PubMed
  2. Picardi M, De Renzo A, Pane F, Nicolai E, Pacelli R, Salvatore M, Rotoli B. Randomized comparison of consolidation radiation versus observation in bulky Hodgkin's lymphoma with post-chemotherapy negative positron emission tomography scans. Leuk Lymphoma. 2007 Sep;48(9):1721-7. link to original article PubMed

Untreated

ABVD

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ABVD: Adriamycin (Doxorubicin), Bleomycin, Vinblastine, Dacarbazine

Regimen #1

Phase III

4-week cycle x 4 to 6 cycles based on stage, response, and whether radiation therapy is used.

References

  1. Bonadonna G, Zucali R, Monfardini S, De Lena M, Uslenghi C. Combination chemotherapy of Hodgkin's disease with adriamycin, bleomycin, vinblastine, and imidazole carboxamide versus MOPP. Cancer. 1975 Jul;36(1):252-9. PubMed
  2. Bonadonna G, Santoro A. ABVD chemotherapy in the treatment of Hodgkin's disease. Cancer Treat Rev. 1982 Mar;9(1):21-35. (no link to original article available) PubMed
  3. Bonadonna G. Chemotherapy strategies to improve the control of Hodgkin's disease: the Richard and Hinda Rosenthal Foundation Award Lecture. Cancer Res. 1982 Nov;42(11):4309-20. link to original article contains protocol PubMed
  4. Santoro A, Bonadonna G, Valagussa P, Zucali R, Viviani S, Villani F, Pagnoni AM, Bonfante V, Musumeci R, Crippa F et al. Long-term results of combined chemotherapy-radiotherapy approach in Hodgkin's disease: superiority of ABVD plus radiotherapy versus MOPP plus radiotherapy. J Clin Oncol. 1987 Jan;5(1):27-37. link to original article PubMed
  5. Carde P, Hagenbeek A, Hayat M, Monconduit M, Thomas J, Burgers MJ, Noordijk EM, Tanguy A, Meerwaldt JH, Le Fur R et al. Clinical staging versus laparotomy and combined modality with MOPP versus ABVD in early-stage Hodgkin's disease: the H6 twin randomized trials from the European Organization for Research and Treatment of Cancer Lymphoma Cooperative Group. J Clin Oncol. 1993 Nov;11(11):2258-72. link to original article PubMed
  6. Engert A, Franklin J, Eich HT, Brillant C, Sehlen S, Cartoni C, Herrmann R, Pfreundschuh M, Sieber M, Tesch H, Franke A, Koch P, de Wit M, Paulus U, Hasenclever D, Loeffler M, Müller RP, Müller-Hermelink HK, Dühmke E, Diehl V. Two cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine plus extended-field radiotherapy is superior to radiotherapy alone in early favorable Hodgkin's lymphoma: final results of the GHSG HD7 trial. J Clin Oncol. 2007 Aug 10;25(23):3495-502. link to original article contains protocol PubMed

B-AVD; AVD-A

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B-AVD: Brentuximab vedotin, Adriamycin (Doxorubicin), Vinblastine, Dacarbazine
AVD-A: Adriamycin (Doxorubicin), Vinblastine, Dacarbazine, Adcetris (Brentuximab vedotin),

Regimen

Study Evidence
Younes et al. 2013 Non-randomized

This was a phase I trial but had >20 patients in the MTD expansion cohort; a phase III trial is underway.

4-week cycle x up to 6 cycles

"Consolidative radiotherapy was permitted at the investigator's discretion."

References

  1. Younes A, Connors JM, Park SI, Fanale M, O'Meara MM, Hunder NN, Huebner D, Ansell SM. Brentuximab vedotin combined with ABVD or AVD for patients with newly diagnosed Hodgkin's lymphoma: a phase 1, open-label, dose-escalation study. Lancet Oncol. 2013 Dec;14(13):1348-56. Epub 2013 Nov 15. link to original article contains verified protocol PubMed
    1. Update: Abstract: Joseph M Connors, MD, Stephen Ansell, Steven I. Park, MD, Michelle A. Fanale, M.D. and Anas Younes. Brentuximab Vedotin Combined with ABVD or AVD for Patients with Newly Diagnosed Advanced Stage Hodgkin Lymphoma: Long Term Outcomes. ASH Annual Meeting 2014, Abstract 292 link to abstract

Brentuximab vedotin (Adcetris)

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Regimen

Study Evidence
Yasenchak et al. 2013 Phase II

21-day cycle up to 16 cycles

References

  1. Abstract: Christopher A. Yasenchak, MD, Robert Chen, MD, Jeff P. Sharman, MD, Ralph V. Boccia, MD, Beata Holkova, MD, Peter J. Rosen, MD, Jonathan W. Friedberg, MD, Megan M. O'Meara, MD and Andres Forero-Torres, MD. A Phase 2 Study Of Single-Agent Brentuximab Vedotin For Front-Line Therapy Of Hodgkin Lymphoma In Patients Age 60 Years and Above: Interim Results. ASH 2013 Abstract 4389 link to abstract
    1. Update: Abstract: Andres Forero-Torres, MD, Beata Holkova, MD, Jeff P. Sharman, MD, Jonathan W. Friedberg, MD, Maurice J. Berkowitz, MD, William Fintel, MD, Robert Chen, MD, Ralph V. Boccia, MD, Mansoor Saleh, MD, Neil Josephson, MD, Maria Corinna Palanca-Wessels, MD, PhD and Christopher A. Yasenchak, MD. Brentuximab Vedotin Monotherapy and in Combination with Dacarbazine in Frontline Treatment of Hodgkin Lymphoma in Patients Aged 60 Years and Above: Interim Results of a Phase 2 Study. ASH 2014 Abstract 294 link to abstract

BV-ABVD

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BV-ABVD: Brentuximab Vedotin, Adriamycin (Doxorubicin), Bleomycin, Vinblastine, Dacarbazine

Regimen

Study Evidence
Federico et al. 2014 Phase II, <20 patients reported

Brentuximab vedotin portion

3-week cycle x 2 cycles, followed by:

ABVD portion

4-week cycle x 3 to 6 cycles based on stage, +/- radiation therapy

References

  1. Abstract: Massimo Federico, Emanuela Anna Pesce, Francesco Merli, Stefano Luminari, Stephane Chauvie, Cinzia Pellegrini, Luigi Marcheselli, Isabella Capodanno, Fiorella Ilariucci, Massimiliano Salati, Lisa Argnani, Pier Luigi Zinzani. A pilot phase II study with brentuximab vedotin followed by ABVD in patients with previously untreated Hodgkin lymphoma: A preliminary report. J Clin Oncol 32:5s, 2014 (suppl; abstr 8507) link to original abstract

ChlVPP

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ChlVPP: Chllorambucil, Vinblastine, Procarbazine, Prednisone

Regimen

Study Evidence
International ChIVPP Treatment Group 1995 Phase II

4-week cycle to complete remission plus 2 cycles; minimum of 6 cycles and maximum of 8 cycles

References

  1. Retrospective: Druker BJ, Rosenthal DS, Canellos GP. Chlorambucil, vinblastine, procarbazine, and prednisone. An effective but less toxic regimen than MOPP for advanced-stage Hodgkin's disease. Cancer. 1989 Mar 15;63(6):1060-4. link to original article PubMed
  2. Selby P, Patel P, Milan S, Meldrum M, Mansi J, Mbidde E, Brada M, Perren T, Forgeson G, Gore M, et al. ChlVPP combination chemotherapy for Hodgkin's disease: long-term results. Br J Cancer. 1990 Aug;62(2):279-85. link to PMC article PubMed
  3. The International ChlVPP Treatment Group. ChlVPP therapy for Hodgkin's disease: experience of 960 patients. Ann Oncol. 1995 Feb;6(2):167-72. link to original article contains protocol PubMed

RABVD

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RABVD: Rituximab, Adriamycin (Doxorubicin), Bleomycin, Vinblastine, Dacarbazine

Regimen #1

Study Evidence
Younes et al. 2012 Phase II

28-day cycle x 6 cycles (except rituximab, which is given for a total of 6 doses)

Regimen #2

Study Evidence
Kasamon et al. 2012 Phase II

28-day cycle x 6 to 8 cycles

References

  1. Younes A, Oki Y, McLaughlin P, Copeland AR, Goy A, Pro B, Feng L, Yuan Y, Chuang HH, Macapinlac HA, Hagemeister F, Romaguera J, Samaniego F, Fanale MA, Dabaja BS, Rodriguez MA, Dang N, Kwak LW, Neelapu SS, Fayad LE. Phase 2 study of rituximab plus ABVD in patients with newly diagnosed classical Hodgkin lymphoma. Blood. 2012 May 3;119(18):4123-8. Epub 2012 Feb 27. link to original article contains protocol PubMed
  2. Kasamon YL, Jacene HA, Gocke CD, Swinnen LJ, Gladstone DE, Perkins B, Link BK, Popplewell LL, Habermann TM, Herman JM, Matsui WH, Jones RJ, Ambinder RF. Phase 2 study of rituximab-ABVD in classical Hodgkin lymphoma. Blood. 2012 May 3;119(18):4129-32. Epub 2012 Feb 16. link to original article contains partial protocol PubMed

VEPEMB

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VEPEMB: Vinblastine, Endoxan (Cyclophosphamide), Procarbazine, Etoposide, Mitoxantrone, Bleomycin

Regimen

Study Evidence
Levis et al. 2004 Phase II

This regimen is intended for elderly patients.

To be completed

References

  1. Levis A, Anselmo AP, Ambrosetti A, Adamo F, Bertini M, Cavalieri E, Gavarotti P, Genua A, Liberati M, Pavone V, Pietrasanta D, Ricetti MM, Scalabrini DR, Salvi F, Vitolo U, Angelucci E, Boccadoro M, Gallo E, Mandelli F; Intergruppo Italiano Linfomi (IIL). VEPEMB in elderly Hodgkin's lymphoma patients. Results from an Intergruppo Italiano Linfomi (IIL) study. Ann Oncol. 2004 Jan;15(1):123-8. link to original article PubMed
    1. Update: Proctor SJ, Wilkinson J, Jones G, Watson GC, Lucraft HH, Mainou-Fowler T, Culligan D, Galloway MJ, Wood KM, McNally RJ, James PW, Goodlad JR. Evaluation of treatment outcome in 175 patients with Hodgkin lymphoma aged 60 years or over: the SHIELD study. Blood. 2012 Jun 21;119(25):6005-15. Epub 2012 May 10. link to original article PubMed

Relapsed/refractory

Bendamustine (Treanda)

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Regimen

Study Evidence
Moskowitz et al. 2013 Phase II

Supportive medications:

28-day cycles x up to 6 cycles

References

  1. Moskowitz AJ, Hamlin PA Jr, Perales MA, Gerecitano J, Horwitz SM, Matasar MJ, Noy A, Palomba ML, Portlock CS, Straus DJ, Graustein T, Zelenetz AD, Moskowitz CH. Phase II Study of Bendamustine in Relapsed and Refractory Hodgkin Lymphoma. J Clin Oncol. 2013 Feb 1;31(4):456-60. Epub 2012 Dec 17. link to original article contains verified protocol PubMed
  2. Retrospective: Anastasia A, Carlo-Stella C, Corradini P, Salvi F, Rusconi C, Pulsoni A, Hohaus S, Pregno P, Viviani S, Brusamolino E, Luminari S, Giordano L, Santoro A. Bendamustine for Hodgkin lymphoma patients failing autologous or autologous and allogeneic stem cell transplantation: a retrospective study of the Fondazione Italiana Linfomi. Br J Haematol. 2014 Mar 7. [Epub ahead of print] link to original article PubMed

Bendamustine & Brentuximab

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Regimen

Study Evidence
LaCasce et al. 2014 Phase II

21-day cycles x up to 6 cycles

References

  1. LaCasce A, Bociek RG, Matous J, et al. Brentuximab Vedotin in Combination with Bendamustine for Patients with Hodgkin Lymphoma who are Relapsed or Refractory after Frontline Therapy. Presented at: 2014 ASH Annual Meeting; December 6-9, 2014; San Francisco, CA. Abstract 293.

Brentuximab vedotin (Adcetris)

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Regimen #1

Study Evidence
Younes et al. 2012 Phase II
Gopal et al. 2012 Non-randomized
Rothe et al. 2012 Retrospective
Moskowitz et al. 2015 (AETHERA) Phase III

Supportive medications:

  • Rothe et al. 2012: "no premedications were administered"
  • Moskowitz et al. 2015: "Infection prophylaxis for herpes simplex virus, varicella-zoster virus, and Pneumocystis jiroveci after autologous stem-cell transplantation were to be followed as per standard international guidelines, and we allowed growth factor and blood product support."

21-day cycles, given until progression (Rothe et al. 2012; Gopal et al. 2012) or up to 16 infusions (Younes et al. 2012; Moskowitz et al. 2015)

Regimen #2

Study Evidence
Moskowitz et al. 2015 Phase II

28-day cycle x 2 cycles

PET-negative patients (a Deauville score of 1 or 2) proceeded to autologous stem cell transplant with BEAM, CBV, or high dose chemoradiotherapy. All others proceeded to receive two cycles of augmented ICE prior to transplant.

References

  1. Younes A, Gopal AK, Smith SE, Ansell SM, Rosenblatt JD, Savage KJ, Ramchandren R, Bartlett NL, Cheson BD, de Vos S, Forero-Torres A, Moskowitz CH, Connors JM, Engert A, Larsen EK, Kennedy DA, Sievers EL, Chen R. Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin's lymphoma. J Clin Oncol. 2012 Jun 20;30(18):2183-9. Epub 2012 Mar 26. link to original article contains verified protocol PubMed
    1. Update: Abstract: Robert Chen, Scott E. Smith, Stephen M Ansell, Joseph D Rosenblatt, Kerry J. Savage, Joseph M. Connors, Andreas Engert, Emily K. Larsen, Dirk Huebner, Eric L. Sievers, Anas Younes. Three-Year Follow-Up Data and Characterization Of Long-Term Remissions From An Ongoing Phase 2 Study Of Brentuximab Vedotin In Patients With Relapsed Or Refractory Hodgkin Lymphoma. Blood Nov 2013,122(21)4382. link to abstract
    2. Update: Abstract: The 12th International Conference on Malignant Lymphoma, Lugano, Switzerland, June 19-20, 2013
    3. Update: Gopal AK, Chen R, Smith SE, Ansell SM, Rosenblatt JD, Savage KJ, Connors JM, Engert A, Larsen EK, Chi X, Sievers EL, Younes A. Durable remissions in a pivotal phase 2 study of brentuximab vedotin in relapsed or refractory Hodgkin lymphoma. Blood. 2014 Dec 22. [Epub ahead of print] link to original article PubMed
  2. Gopal AK, Ramchandren R, O'Connor OA, Berryman RB, Advani RH, Chen R, Smith SE, Cooper M, Rothe A, Matous JV, Grove LE, Zain J. Safety and efficacy of brentuximab vedotin for Hodgkin lymphoma recurring after allogeneic stem cell transplantation. Blood. 2012 Jul 19;120(3):560-8. Epub 2012 Apr 17. link to original article contains verified protocol PubMed
  3. Retrospective: Rothe A, Sasse S, Goergen H, Eichenauer DA, Lohri A, Jäger U, Bangard C, Böll B, von Bergwelt Baildon M, Theurich S, Borchmann P, Engert A. Brentuximab vedotin for relapsed or refractory CD30+ hematologic malignancies: the German Hodgkin Study Group experience. Blood. 2012 Aug 16;120(7):1470-2. Epub 2012 Jul 11. link to original article contains verified protocol PubMed
  4. Gibb A, Jones C, Bloor A, Kulkarni S, Illidge T, Linton K, Radford J. Brentuximab vedotin in refractory CD30+ lymphomas: a bridge to allogeneic transplantation in approximately one quarter of patients treated on a Named Patient Programme at a single UK center. Haematologica. 2013 Apr;98(4):611-4. Epub 2012 Oct 12. link to original article contains verified protocol PubMed
  5. Moskowitz AJ, Schöder H, Yahalom J, McCall SJ, Fox SY, Gerecitano J, Grewal R, Hamlin PA, Horwitz S, Kobos R, Kumar A, Matasar M, Noy A, Palomba ML, Perales MA, Portlock CS, Sauter C, Shukla N, Steinherz P, Straus D, Trippett T, Younes A, Zelenetz A, Moskowitz CH. PET-adapted sequential salvage therapy with brentuximab vedotin followed by augmented ifosamide, carboplatin, and etoposide for patients with relapsed and refractory Hodgkin's lymphoma: a non-randomised, open-label, single-centre, phase 2 study. Lancet Oncol. 2015 Mar;16(3):284-92. Epub 2015 Feb 13. link to original article contains protocol PubMed
  6. Moskowitz CH, Nademanee A, Masszi T, Agura E, Holowiecki J, Abidi MH, Chen AI, Stiff P, Gianni AM, Carella A, Osmanov D, Bachanova V, Sweetenham J, Sureda A, Huebner D, Sievers EL, Chi A, Larsen EK, Hunder NN, Walewski J; AETHERA Study Group. Brentuximab vedotin as consolidation therapy after autologous stem-cell transplantation in patients with Hodgkin's lymphoma at risk of relapse or progression (AETHERA): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2015 May 9;385(9980):1853-62. link to original article contains verified protocol PubMed

DHAP

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DHAP: Dexamethasone, High-dose Ara-C (Cytarabine), Platinol (Cisplatin)

Regimen

Study Evidence
Valesquez et al. 1988 Phase II
Sureda et al. 2011 Phase II

Supportive medications:

  • Normal saline with mannitol 50 g/L given at 250 mL/H x 36 hours, starting 6 hours before Cisplatin (Platinol) infusion was started

21 to 28-day cycles (depending on degree of myelosuppression)

Velasquez et al. 1988 gave 6 to 10 cycles, with therapy given 4 cycles beyond the maximum antitumor effect. Sureda et al. 2011 gave 2 cycles, with responders proceeding to RIC allogeneic stem cell transplant.

  • Aside from the table below (from Velasquez et al. 1988), there were no specific cutoff criteria about dose modifications or delays of treatment.

Dose modifications:

Dose modifications
Event Cytarabine (Cytosar) Cisplatin (Platinol)
ANC <200 1000 mg/m2 x 2 doses 100 mg/m2
Platelets <20 x 10^3 1000 mg/m2 x 2 doses 100 mg/m2
Sepsis associated with neutropenia 500 mg/m2 x 1 dose 100 mg/m2
Cr 1.5 to 2.0 - 75 mg/m2
Cr 2.1-3.0 - 50 mg/m2

References

  1. Velasquez WS, Cabanillas F, Salvador P, McLaughlin P, Fridrik M, Tucker S, Jagannath S, Hagemeister FB, Redman JR, Swan F, Barlogie B. Effective salvage therapy for lymphoma with cisplatin in combination with high-dose Ara-C and dexamethasone (DHAP). Blood. 1988 Jan;71(1):117-22. link to original article contains protocol PubMed
  2. Sureda A, Canals C, Arranz R, Caballero D, Ribera JM, Brune M, Passweg J, Martino R, Valcárcel D, Besalduch J, Duarte R, León A, Pascual MJ, García-Noblejas A, López Corral L, Xicoy B, Sierra J, Schmitz N. Allogeneic stem cell transplantation after reduced intensity conditioning in patients with relapsed or refractory Hodgkin's lymphoma. Results of the HDR-ALLO study - a prospective clinical trial by the Grupo Español de Linfomas/Trasplante de Médula Osea (GEL/TAMO) and the Lymphoma Working Party of the European Group for Blood and Marrow Transplantation. Haematologica. 2012 Feb;97(2):310-7. Epub 2011 Oct 11. link to original article contains protocol PubMed

DHAP - time intensified

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DHAP: Dexamethasone, High-dose Ara-C (Cytarabine), Platinol (Cisplatin)

Regimen

Study Evidence
Josting et al. 2002 Phase II

This was used as a salvage regimen for relapsed/refractory Hodgkin Lymphoma in patients who were planned for high-dose chemotherapy (HDCT) and autologous stem cell transplantation.

Supportive medications:

Variable number of days between cycles depending on count recovery x 2 cycles Median time between cycle 1 and 2 was 16 days. The paper did not definitively specify what criteria needed to be fulfilled before cycle 2 was given. Baseline eligibility criteria for the study included WBC >3.5 x 10^3, Hb =8, platelets =100 x 10^3.

References

  1. Josting A, Rudolph C, Reiser M, Mapara M, Sieber M, Kirchner HH, Dörken B, Hossfeld DK, Diehl V, Engert A; Participating Centers. Time-intensified dexamethasone/cisplatin/cytarabine: an effective salvage therapy with low toxicity in patients with relapsed and refractory Hodgkin's disease. Ann Oncol. 2002 Oct;13(10):1628-35. link to original article contains protocol PubMed

Everolimus (Afinitor)

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Regimen

Study Evidence
Johnston et al. 2010 Phase II

Supportive medications:

  • "Patients could receive white blood cell growth factors if neutropenia developed. Erythropoietin treatment for anemia was permitted."

28-day cycles, given until progression or unacceptable toxicity

References

  1. Johnston PB, Inwards DJ, Colgan JP, Laplant BR, Kabat BF, Habermann TM, Micallef IN, Porrata LF, Ansell SM, Reeder CB, Roy V, Witzig TE. A Phase II trial of the oral mTOR inhibitor everolimus in relapsed Hodgkin lymphoma. Am J Hematol. 2010 May;85(5):320-4. link to original article contains verified protocol PubMed

GCD +/- R

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GCD +/- R: Gemcitabine, Carboplatin, Dexamethasone, Rituximab

Regimen

Study Evidence
Gopal et al. 2010 Phase II

Supportive medications:

  • Growth factor support and antibiotic prophylaxis used is at the discretion of the treating physician.

3-week cycle x up to 4 cycles

Dose modifications:

  • If on day 8, platelets are 50 to 100 or ANC 500 to 1000: reduce Gemcitabine (Gemzar) dose by 25% for that dose only.
  • If on day 8, platelets are <50 or ANC <500: No day 8 Gemcitabine (Gemzar) dose given.
  • Subsequent cycles would be given at full dose if patients had platelets <50 or ANC <1000.
  • If counts were not adequate, the next cycle can be delayed for up to 3 weeks until counts are adequate for treatment.

References

  1. Gopal AK, Press OW, Shustov AR, Petersdorf SH, Gooley TA, Daniels JT, Garrison MA, Gjerset GF, Lonergan M, Murphy AE, Smith JC, Pagel JM. Efficacy and safety of gemcitabine, carboplatin, dexamethasone, and rituximab in patients with relapsed/refractory lymphoma: a prospective multi-center phase II study by the Puget Sound Oncology Consortium. Leuk Lymphoma. 2010 Aug;51(8):1523-9. link to PMC article contains protocol PubMed

Gemcitabine (Gemzar)

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Regimen

Study Evidence
Santoro et al. 2000 Phase II
  • Gemcitabine (Gemzar) as follows:
    • Cycle 1: 1250 mg/m2 IV over 30 minutes once per day on days 1, 8, 15
    • Subsequent cycles (if no hematologic or nonhematologic toxicities): 1500 mg/m2 IV over 30 minutes once per day on days 1, 8, 15

4-week cycles until progression or intolerance

References

  1. Santoro A, Bredenfeld H, Devizzi L, Tesch H, Bonfante V, Viviani S, Fiedler F, Parra HS, Benoehr C, Pacini M, Bonadonna G, Diehl V. Gemcitabine in the treatment of refractory Hodgkin's disease: results of a multicenter phase II study. J Clin Oncol. 2000 Jul;18(13):2615-9. link to original article contains verified protocol PubMed

GVD

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GVD: Gemcitabine, Vinorelbine, Doxil (Liposomal doxorubicin)

Regimen

Study Evidence
Bartlett et al. 2007 (CALGB 59804) Phase II

Transplant-naive patients

3-week cycle x 2 to 6 cycles

Post-transplant patients

3-week cycle x 2 to 6 cycles

Dose levels: Note: These dose levels are listed primarily for historical purposes and were used in the trial while dose levels and dose limiting toxicities (DLT) and maximum tolerated dose (MTD) were being determined. The MTD dosages used above correspond to dose level 1 for transplant-naive patients and dose level -1 for post-transplant patients.

Dose modifications:

  • If on day 8, platelets are 50 to 100 or ANC 500 to 1000: reduce Gemcitabine (Gemzar) dose by 25% for that dose only.
  • If on day 8, platelets are <50 or ANC <500: No day 8 Gemcitabine (Gemzar) dose given.
  • Subsequent cycles would be given at full dose if patients had platelets =50 or ANC =1000.
  • If counts were not adequate, the next cycle can be delayed for up to 3 weeks until counts are adequate for treatment.

References

  1. Bartlett NL, Niedzwiecki D, Johnson JL, Friedberg JW, Johnson KB, van Besien K, Zelenetz AD, Cheson BD, Canellos GP; Cancer Leukemia Group B. Gemcitabine, vinorelbine, and pegylated liposomal doxorubicin (GVD), a salvage regimen in relapsed Hodgkin's lymphoma: CALGB 59804. Ann Oncol. 2007 Jun;18(6):1071-9. link to original article contains protocol PubMed

GVP

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GVP: Gemcitabine, Vinorelbine, Prednisolone

Regimen

Study Evidence
Naqi et al. 2013 Phase II

28-day cycle x 4 cycles

References

  1. Naqi N, Ahmad S, Shah I, Khattak J. A multicentre phase-II feasibility study evaluating gemcitabine/vinorelbine / prednisolone combination chemotherapy in relapsed / refractory Hodgkin's lymphoma. J Coll Physicians Surg Pak. 2013 Jun;23(6):397-400. PubMed

ICE

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ICE: Ifosfamide, Carboplatin, Etoposide

Regimen #1

Study Evidence
Moskowitz et al. 2001 Phase II

Supportive medications:

  • Mesna (Mesnex) 5000 mg/m2 IV continuous infusion over 24 hours on day 2; mixed in same solution as Ifosfamide (Ifex)
  • Filgrastim (Neupogen) 5 mcg/kg SC once per day on days 5 to 12
  • No dose reductions--treatment is delayed until ANC is >1000 and platelets >50 x 10^3

2-week cycle x 2 cycles

Regimen #2, "Augmented ICE"

Study Evidence
Moskowitz et al. 2015 Phase II

Treatment preceded by brentuximab vedotin.

Supportive medications:

2 cycles

Autologous stem cell transplant was "considered" after 2 cycles; criteria not listed in the abstract.

References

  1. Moskowitz CH, Nimer SD, Zelenetz AD, Trippett T, Hedrick EE, Filippa DA, Louie D, Gonzales M, Walits J, Coady-Lyons N, Qin J, Frank R, Bertino JR, Goy A, Noy A, O'Brien JP, Straus D, Portlock CS, Yahalom J. A 2-step comprehensive high-dose chemoradiotherapy second-line program for relapsed and refractory Hodgkin disease: analysis by intent to treat and development of a prognostic model. Blood. 2001 Feb 1;97(3):616-23. link to original article contains protocol PubMed
  2. Moskowitz AJ, Schöder H, Yahalom J, McCall SJ, Fox SY, Gerecitano J, Grewal R, Hamlin PA, Horwitz S, Kobos R, Kumar A, Matasar M, Noy A, Palomba ML, Perales MA, Portlock CS, Sauter C, Shukla N, Steinherz P, Straus D, Trippett T, Younes A, Zelenetz A, Moskowitz CH. PET-adapted sequential salvage therapy with brentuximab vedotin followed by augmented ifosamide, carboplatin, and etoposide for patients with relapsed and refractory Hodgkin's lymphoma: a non-randomised, open-label, single-centre, phase 2 study. Lancet Oncol. 2015 Mar;16(3):284-92. Epub 2015 Feb 13. link to original article contains protocol PubMed

Ifosfamide & Vinorelbine

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Regimen

Study Evidence
Bonfante et al. 1998 Phase II

Supportive medications:

3-week cycles

References

  1. Bonfante V, Viviani S, Santoro A, Devizzi L, Di Russo A, Zanini M, Soncini F, Soto Parra H, Valagussa P, Bonadonna G. Ifosfamide and vinorelbine: an active regimen for patients with relapsed or refractory Hodgkin's disease. Br J Haematol. 1998 Nov;103(2):533-5. link to original article contains verified protocol PubMed
  2. Bonfante V, Viviani S, Devizzi L, Di Russo A, Di Nicola M, Magni M, Matteucci P, Grisanti S, Valagussa P, Bonadonna G, Gianni AM. High-dose ifosfamide and vinorelbine as salvage therapy for relapsed or refractory Hodgkin's disease. Eur J Haematol Suppl. 2001 Jul;64:51-5. contains protocol PubMed

IGEV

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IGEV: Ifosfamide, GEmcitabine, Vinorelbine

Regimen

Study Evidence
Santoro et al. 2007 Phase II

Supportive medications:

  • 2L saline solution hyperhydration days 1 to 4
  • Mesna (Mesnex) 2600 mg/m2 IV once per day on days 1 to 4
  • Filgrastim (Neupogen) (dose not specified, but could assume 5 mcg/kg) SC once per day on days 7 to 12, or up to apheresis in the course of stem cell mobilization

21-day cycle x 4 cycles

References

  1. Santoro A, Magagnoli M, Spina M, Pinotti G, Siracusano L, Michieli M, Nozza A, Sarina B, Morenghi E, Castagna L, Tirelli U, Balzarotti M. Ifosfamide, gemcitabine, and vinorelbine: a new induction regimen for refractory and relapsed Hodgkin's lymphoma. Haematologica. 2007 Jan;92(1):35-41. link to original article contains verified protocol PubMed

MINE

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MINE: Mesna, Ifosfamide, Novantrone (Mitoxantrone), Etoposide

Regimen

Study Evidence
Rodriguez et al. 1995 Phase II

3 to 4-week cycle x up to 6 cycles in responding patients

References

  1. Rodriguez MA, Cabanillas FC, Hagemeister FB, McLaughlin P, Romaguera JE, Swan F, Velasquez W. A phase II trial of mesna/ifosfamide, mitoxantrone and etoposide for refractory lymphomas. Ann Oncol. 1995 Jul;6(6):609-11. link to original article contains protocol PubMed

Mini-BEAM

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BEAM: BiCNU (Carmustine), Etoposide, Ara-C (Cytarabine), Melphalan

Regimen #1

Study Evidence
Fernández-Jiménez et al. 1999 Phase II

4-week cycle x 2 to 3 cycles

Regimen #2

Study Evidence
Colwill et al. 1995 Phase II

Supportive medications:

  • If febrile neutropenia occurred during previous cycle: Ciprofloxacin (Cipro) 500 mg PO once per day
  • Patients were transfused to keep Hb ≥8, platelets ≥20
  • There was no routine use of G-CSF or GM-CSF

4 to 6 week cycles, depending on hematologic recovery

Patients eligible for autologous stem cell transplant received no more than 2 cycles; otherwise total # of cycles not reported

References

  1. Colwill R, Crump M, Couture F, Danish R, Stewart AK, Sutton DM, Scott JG, Sutcliffe SB, Brandwein JM, Keating A. Mini-BEAM as salvage therapy for relapsed or refractory Hodgkin's disease before intensive therapy and autologous bone marrow transplantation. J Clin Oncol. 1995 Feb;13(2):396-402. link to original article contains protocol PubMed
  2. Fernández-Jiménez MC, Canales MA, Ojeda E, de Bustos JG, Aguado MJ, Hernández-Navarro F. Salvage chemotherapy with mini-BEAM for relapsed or refractory Hodgkin's disease prior to autologous peripheral blood stem cell transplantation. Haematologica. 1999 Nov;84(11):1007-11. link to original article contains verified protocol PubMed
    1. Update: Martín A, Fernández-Jiménez MC, Caballero MD, Canales MA, Pérez-Simón JA, García de Bustos J, Vázquez L, Hernández-Navarro F, San Miguel JF. Long-term follow-up in patients treated with Mini-BEAM as salvage therapy for relapsed or refractory Hodgkin's disease. Br J Haematol. 2001 Apr;113(1):161-71. link to original article contains protocol PubMed

Nivolumab (Opdivo)

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Regimen

Study Evidence
Ansell et al. 2014 Non-randomized

Continued until disease progression, or complete response, or up to 2 years

References

  1. Ansell SM, Lesokhin AM, Borrello I, Halwani A, Scott EC, Gutierrez M, Schuster SJ, Millenson MM, Cattry D, Freeman GJ, Rodig SJ, Chapuy B, Ligon AH, Zhu L, Grosso JF, Kim SY, Timmerman JM, Shipp MA, Armand P. PD-1 Blockade with Nivolumab in Relapsed or Refractory Hodgkin's Lymphoma. N Engl J Med. 2015 Jan 22;372(4):311-9. Epub 2014 Dec 6. link to original article contains verified protocol PubMed

Sirolimus & Vorinostat

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Regimen

Study Evidence
Janku et al. 2014 Non-randomized

This is a very heavily pre-treated cohort, median of 6 prior therapies; doses here are one level below MTD and are proposed as the ongoing doses to be studied.

28-day cycles

References

  1. Abstract: Filip Janku, Yasuhiro Oki, Gerald Steven Falchook, Vivek Subbiah, Aung Naing, Vivianne Marie Velez Bravo, David S. Hong, Jason R. Westin, Cesar Nunez, Luis Fayad, Sattva Swarup Neelapu, Larry W. Kwak, Elizabeth J. Shpall, Jennifer J. Wheler, Tamara Barnes, Winnie S. Liang, Bodour Salhia, Funda Meric-Bernstam, Razelle Kurzrock, Michelle A. Fanale. Activity of the mTOR inhibitor sirolimus and HDAC inhibitor vorinostat in heavily pretreated refractory Hodgkin lymphoma patients. J Clin Oncol 32:5s, 2014 (suppl; abstr 8508) link to original abstract

Vinorelbine (Navelbine)

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Regimen

Study Evidence
Devizzi et al. 1994 Phase II

The definition of a cycle is not clear from the abstract. Complete responders underwent a time-limited duration of therapy, whereas others continued until progression.

References

  1. Devizzi L, Santoro A, Bonfante V, Viviani S, Balzarini L, Valagussa P,vBonadonna G. Vinorelbine: an active drug for the management of patients withvheavily pretreated Hodgkin's disease. Ann Oncol. 1994 Nov;5(9):817-20. link to original article PubMed

Consolidation and/or maintenance after salvage therapy

Allogeneic stem cell transplant

Usually reserved for patients relapsing after autologous stem cell transplant, and then for younger and very fit individuals. The regimens below have been specifically studied in the setting of relapsed/refractory Hodgkin lymphoma; for other regimens please go to the transplant conditioning regimens page.

Regimen #1

To be completed. Treatment preceded by salvage brentuximab vedotin.

Regimen #2

Study Evidence
Sureda et al. 2011 Phase II

Treatment preceded by DHAP x 2.

Recipients of stem cells from matched unrelated donors also received:

Graft-versus-host disease prophylaxis

  • Cyclosporine A (not specified whether modified or non-modified) starting at 1.5 mg/kg BID IV on day -2
  • Methotrexate (MTX) 10 mg/m2 IV once per day on days +1, +3, +6, +11

If no acute GVHD of grade 2 or more, cyclosporine A is tapered down by 10% per week starting on day +90 with planned discontinuation by day +180.

Regimen #3

Study Evidence
Anderlini et al. 2008 Phase II

Patients had "chemosensitive or stable disease after salvage treatment." The regimen as reported here is what the authors were using towards the end of the study period; see paper for details.

Recipients of stem cells from matched unrelated donors also received:

Graft-versus-host disease prophylaxis

  • Tacrolimus (Prograf) IV starting on day -2, dosed to achieve serum levels 4–12 ng/mL and switched to PO as soon as possible. Continued for at least 6 months and then "tapered off" (instructions not given).
  • Methotrexate (MTX) 5 mg/m2 IV once per day on days +1, +3, +6 (extra dose on day +11 for MUD recipients)

Regimen #4

Study Evidence
Sobol et al. 2013 Phase II

BEAM is the preparative regimen; further details not available in the abstract.

References

  1. Alvarez I, Sureda A, Caballero MD, Urbano-Ispizua A, Ribera JM, Canales M, García-Conde J, Sanz G, Arranz R, Bernal MT, de la Serna J, Díez JL, Moraleda JM, Rubió-Félix D, Xicoy B, Martínez C, Mateos MV, Sierra J. Nonmyeloablative stem cell transplantation is an effective therapy for refractory or relapsed hodgkin lymphoma: results of a spanish prospective cooperative protocol. Biol Blood Marrow Transplant. 2006 Feb;12(2):172-83. link to original article contains protocol PubMed
  2. Anderlini P, Saliba R, Acholonu S, Giralt SA, Andersson B, Ueno NT, Hosing C, Khouri IF, Couriel D, de Lima M, Qazilbash MH, Pro B, Romaguera J, Fayad L, Hagemeister F, Younes A, Munsell MF, Champlin RE. Fludarabine-melphalan as a preparative regimen for reduced-intensity conditioning allogeneic stem cell transplantation in relapsed and refractory Hodgkin's lymphoma: the updated M.D. Anderson Cancer Center experience. Haematologica. 2008 Feb;93(2):257-64. Epub 2008 Jan 26. link to original article contains verified protocol PubMed
  3. Sureda A, Canals C, Arranz R, Caballero D, Ribera JM, Brune M, Passweg J, Martino R, Valcárcel D, Besalduch J, Duarte R, León A, Pascual MJ, García-Noblejas A, López Corral L, Xicoy B, Sierra J, Schmitz N. Allogeneic stem cell transplantation after reduced intensity conditioning in patients with relapsed or refractory Hodgkin's lymphoma. Results of the HDR-ALLO study - a prospective clinical trial by the Grupo Español de Linfomas/Trasplante de Médula Osea (GEL/TAMO) and the Lymphoma Working Party of the European Group for Blood and Marrow Transplantation. Haematologica. 2012 Feb;97(2):310-7. Epub 2011 Oct 11. link to original article contains verified protocol PubMed
  4. Sobol U, Rodriguez T, Smith S, Go A, Vimr R, Parthasarathy M, Guo R, Stiff P. Seven-year follow-up of allogeneic transplant using BCNU, etoposide, cytarabine and melphalan chemotherapy in patients with Hodgkin lymphoma after autograft failure: importance of minimal residual disease. Leuk Lymphoma. 2014 Jun;55(6):1281-7. Epub 2013 Oct 3. link to original article PubMed
  5. Illidge T, Bouabdallah R, Chen R, Gopal AK, Moskowitz CH, Ramchandren R, Shustov AR, Tilly H, Trippett TM, Gibb A, Grove LE, Advani R. Allogeneic transplant following brentuximab vedotin in patients with relapsed or refractory Hodgkin lymphoma and systemic anaplastic large cell lymphoma. Leuk Lymphoma. 2015 Jan 21:1-8. [Epub ahead of print] link to original article PubMed

Autologous stem cell transplant

To be completed. Usually preceded by a high-intensity salvage chemotherapy. See details about preparative regimens.

Brentuximab vedotin (Adcetris)

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Regimen

Study Evidence Comparator
Moskowitz et al. 2015 (AETHERA) Phase III Placebo

Treatment begins 30 to 45 days after autologous stem cell transplant.

3-week cycle x 16 cycles

References

  1. Moskowitz CH, Nademanee A, Masszi T, Agura E, Holowiecki J, Abidi MH, Chen AI, Stiff P, Gianni AM, Carella A, Osmanov D, Bachanova V, Sweetenham J, Sureda A, Huebner D, Sievers EL, Chi A, Larsen EK, Hunder NN, Walewski J; AETHERA Study Group. Brentuximab vedotin as consolidation therapy after autologous stem-cell transplantation in patients with Hodgkin's lymphoma at risk of relapse or progression (AETHERA): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2015 Mar 18. [Epub ahead of print] link to original article contains verified protocol PubMed

Observation

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Regimen

Study Evidence Comparator
Moskowitz et al. 2015 (AETHERA) Phase III Brentuximab vedotin

No further treatment after autologous stem cell transplant.

References

  1. Moskowitz CH, Nademanee A, Masszi T, Agura E, Holowiecki J, Abidi MH, Chen AI, Stiff P, Gianni AM, Carella A, Osmanov D, Bachanova V, Sweetenham J, Sureda A, Huebner D, Sievers EL, Chi A, Larsen EK, Hunder NN, Walewski J; AETHERA Study Group. Brentuximab vedotin as consolidation therapy after autologous stem-cell transplantation in patients with Hodgkin's lymphoma at risk of relapse or progression (AETHERA): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2015 Mar 18. [Epub ahead of print] link to original article contains verified protocol PubMed

Nodular lymphocyte predominant Hodgkin Lymphoma

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